Absorbable soft artificial bone material and preparation method thereof

Abstract

The application discloses absorbable soft artificial bone material and a preparation method thereof, and relates to the technical field of medical materials.The absorbable soft artificial bone material comprises the following raw materials in parts by weight: bioactive glass 30-60 parts, collagen 20-50 parts, reinforcing agent 10-30 parts, antibacterial agent 1-3 parts, pore-forming agent 5-10 parts, and deionized water 100-180 parts.The absorbable soft artificial bone material prepared by the application has good compressive strength and fracture toughness and excellent antibacterial performance.

Description

Technical Field

[0001] This invention relates to the field of medical materials technology, specifically to an absorbable soft artificial bone material and its preparation method. Background Technology

[0002] Bone tissue injury, bone defects, and impaired bone regeneration are common clinical problems. Currently, commonly used bone repair materials include autologous bone, allogeneic bone, xenogeneic bone, and various synthetic bone substitutes. Among existing artificial bone materials, ceramic materials such as hydroxyapatite and β-tricalcium phosphate are representative. While they possess high mechanical strength, they are also brittle, making it difficult to meet the mechanical adaptation requirements of soft tissue attachment areas or irregular bone defects under pressure and deformation conditions. In recent years, bioactive glass has attracted widespread attention in bone repair materials due to its ability to release bioactive ions in the body fluid environment, inducing the formation of a bone-like apatite mineralization layer and promoting osteoblast adhesion, proliferation, and differentiation. However, pure bioactive glass is usually quite brittle and hard. If used directly as a block implant material, it is prone to fracture under load, lacking flexibility and compressibility, making it unsuitable for fitting complex-shaped bone defect areas. To improve the flexibility and biocompatibility of materials, bioactive glass is often combined with collagen, gelatin, chitosan or polylactic acid-based degradable polymers. However, existing composite materials still have problems such as insufficient compressive strength and poor antibacterial effect. Therefore, it is of great significance to develop a soft artificial bone material with good compressive strength, flexibility and antibacterial properties.

[0003] Chinese invention patent CN120285301A discloses an artificial bone composite material and its preparation method. The preparation method includes: adding CaCl2 solution and NaH2PO4 solution sequentially to a collagen solution in a certain proportion to adjust the pH to 7.4, and collecting a white gel-like substance. The white gel-like substance is dispersed in distilled water to obtain colloid one. Colloid one and modified polyetheretherketone powder are added in a certain proportion to a dichloromethane solution containing L-polylactic acid to obtain mixture two. Ethanol solution is then added for precipitation, and the precipitate in mixture two is removed to obtain a slurry. The slurry is injected into a mold to obtain intermediate one, which is then immersed in an EDC / NHS ethanol solution for crosslinking. This preparation method can produce an artificial bone composite material with high mechanical strength and good biocompatibility, overcoming the limitation of existing artificial bone composite materials where biocompatibility and mechanical strength cannot be simultaneously achieved, thus improving the practicality of artificial bone composite materials. However, its antibacterial properties are still insufficient. Summary of the Invention

[0004] In view of the shortcomings of the existing technology, the purpose of this invention is to provide an absorbable soft artificial bone material and its preparation method.

[0005] To achieve the above objectives, the present invention provides the following technical solution:

[0006] An absorbable soft artificial bone material, comprising the following raw materials in parts by weight:

[0007] Bioactive glass 30-60 parts, collagen 20-50 parts, reinforcing agent 10-30 parts, antibacterial agent 1-3 parts, pore-forming agent 5-10 parts, deionized water 100-180 parts;

[0008] The reinforcing agent is prepared by the following method:

[0009] S1: Tris(4-hydroxyphenyl)amine reacts with epichlorohydrin to produce tris[4-(epoxypropane-2-ylmethoxy)phenyl]amine, and the reaction equation is shown below:

[0010]

[0011] S2: Tris[4-(epoxypropane-2-ylmethoxy)phenyl]amine reacts with 2,5,8,11,14,17,20,23,26,29-decoxahexane-31-thiol to form a thioether compound. The reaction equation is shown below:

[0012]

[0013] S3: The reaction of thioether compounds with phosphorylacetic acid produces an enhancer, and the reaction equation is shown below:

[0014]

[0015] The antibacterial agent is prepared by the following method:

[0016] N1: 2-Quinolinhexanoic acid reacts with 9-octadecenamine to generate intermediate 1, and the reaction equation is shown below:

[0017]

[0018] N2: Intermediate 1 is converted into intermediate 2 under the action of m-chloroperoxybenzoic acid, and the reaction equation is shown below:

[0019]

[0020] N3: Intermediate 2 reacts with 1-methyl-3-(3-aminopropyl)-3-chloroimidazolium to generate intermediate 3, and the reaction equation is shown below:

[0021]

[0022] N4: Intermediate 3 reacts with 2-(3,4,5-trihydroxyphenyl)acetic acid to generate an antibacterial agent. The reaction equation is shown below:

[0023]

[0024] In step S1, the molar ratio of tris(4-hydroxyphenyl)amine to epichlorohydrin is 1:(3.05-3.1).

[0025] In step S2, the molar ratio of the tris[4-(epoxypropane-2-ylmethoxy)phenyl]amine to 2,5,8,11,14,17,20,23,26,29-decoxatricarboxane-31-thiol is 1:(3.1-3.2).

[0026] In step S3, the molar ratio of the thioether compound to phosphorylated acetic acid is 1:(3.1-3.3).

[0027] In step N1, the molar ratio of 2-quinolinococcaenoic acid to 9-octadeceneamine is 1:1.05.

[0028] In step N2, the molar ratio of intermediate 1 to m-chloroperoxybenzoic acid is 1:1.2.

[0029] In step N3, the molar ratio of intermediate 2 to 1-methyl-3-(3-aminopropyl)-3-chloroimidazolium is 2.05:1.

[0030] In step N4, the molar ratio of intermediate 3 to 2-(3,4,5-trihydroxyphenyl)acetic acid is 1:2.1.

[0031] The collagen is recombinant human collagen; the pore-forming agent is sodium chloride.

[0032] A method for preparing an absorbable soft artificial bone material includes the following steps:

[0033] (1) Weigh out the following by weight: 30-60 parts of bioactive glass, 20-50 parts of collagen, 10-30 parts of reinforcing agent, 1-3 parts of antibacterial agent, 5-10 parts of pore-forming agent, and 100-180 parts of deionized water;

[0034] (2) Mix deionized water and collagen, add bioactive glass, reinforcing agent, antibacterial agent and pore-forming agent, and stir to form a slurry; inject the slurry into a polytetrafluoroethylene mold, and demold after vacuum degassing and freeze drying to obtain absorbable soft artificial bone material.

[0035] Due to the adoption of the above technical solutions, the beneficial effects of the present invention include:

[0036] The absorbable soft artificial bone material prepared by this invention exhibits good compressive strength, fracture toughness, and excellent antibacterial properties. Specifically, the added reinforcing agent synergistically enhances the compressive strength and fracture toughness of the bone material through the rigid structure of triphenylamine, the long flexible ether chain structure, and the phosphoryl group; the added antibacterial agent synergistically enhances the antibacterial properties of the bone material through the imidazolium cation, long-chain alkyl group, quinoline heterocyclic structure, and multiple phenolic hydroxyl groups. Attached Figure Description

[0037] Figure 1 The proton NMR spectrum of intermediate 1 prepared in Example 4;

[0038] Figure 2 The proton NMR spectrum of intermediate 2 prepared in Example 4;

[0039] Figure 3 The proton NMR spectrum of intermediate 3 prepared in Example 4;

[0040] Figure 4 The image shows the proton NMR spectrum of the antibacterial agent prepared in Example 4. Detailed Implementation

[0041] The following description, in conjunction with specific embodiments, provides further details, but the present invention is not limited to these embodiments.

[0042] Example 1: Preparation of the reinforcing agent:

[0043] S1: Under nitrogen protection, 250 ml of DMF, 0.1 mol of tris(4-hydroxyphenyl)amine, 0.305 mol of epichlorohydrin, and 9 mmol of tetrabutylammonium bromide were stirred and mixed thoroughly. The mixture was reacted at 80 °C for 5 h, then cooled to 65 °C, and 60 g of 20 wt% sodium hydroxide solution was slowly added dropwise over 50 min. The mixture was then cooled to room temperature and the reaction continued for 12 h. The mixture was then distilled under reduced pressure at 70 °C for 1 h, and 500 ml of cold n-hexane was added and stirred to precipitate the precipitate. The precipitate was filtered, washed with deionized water (3 × 100 ml), and dried under vacuum at 70 °C for 12 h to obtain tris[4-(epoxypropane-2-ylmethoxy)phenyl]amine. Its 1H NMR data are as follows: 1 H NMR (400 MHz, Chloroform- d ) δ 7.20-7.12(m, 6H), 6.97-6.90 (m, 6H), 4.22-4.07 (m, 6H), 3.65 (s, 3H), 2.89 (dd, J =4.8, 5.0 Hz, 6H);

[0044] S2: Mix 1000 ml anhydrous DMF, 0.1 mol tris[4-(epoxypropane-2-ylmethoxy)phenyl]amine, 0.31 mol 2,5,8,11,14,17,20,23,26,29-decaoxane-31-thiol, and 0.31 mol triethylamine. Heat to 60 °C and react for 5 h. Cool to room temperature, add 1200 ml deionized water to the reaction mixture, and extract with dichloromethane (3 × 400 ml). Combine the organic phases and extract with 200 ml of dichloromethane sequentially. The product was washed with 5wt% dilute hydrochloric acid solution, 200ml saturated sodium bicarbonate solution, and 200ml saturated brine. After drying with 20g anhydrous sodium sulfate, the mixture was filtered and rotary evaporated at 35℃ for 2h to obtain the crude product. The crude product was dissolved in 400ml ethyl acetate, and 800ml cold n-hexane was slowly added with stirring to precipitate the product. The precipitate was filtered, and the filter cake was washed with cold n-hexane (3×100ml). The precipitate was then dried under vacuum at 45℃ for 12h to obtain the sulfide compound. Its 1H NMR data are as follows: 1 H NMR (400 MHz, DMSO- d 6 ) δ7.23-7.15 (m, 6H), 6.99-6.92 (m, 6H), 5.16 (d, J = 5.0 Hz, 3H), 4.04-3.99 (m,3H), 3.98 (d, J = 3.0 Hz, 6H), 3.71-3.50 (m, 114H), 3.30 (s, 9H), 2.72-2.53(m, 12H);

[0045] S3: Under nitrogen protection, 1200 ml of anhydrous tetrahydrofuran, 0.1 mol of thioether compound, and 0.31 mol of phosphorylated acetic acid were stirred and mixed. Then, 0.31 mol of dicyclohexylcarbodiimide and 0.06 mol of 4-dimethylaminopyridine were added, and the mixture was stirred for 15 min. The reaction was carried out at 25 °C for 18 h. After filtration, 2000 ml of cold n-hexane was added to the filtrate, and the mixture was stirred to precipitate the precipitate. After filtration, the filter cake was treated with a cold methanol-water mixture (V... 甲醇 :V 水 Wash with a 4:1 ratio (3 x 100 ml) solution, followed by 600 ml of a dichloromethane and methanol mixture (V... 二氯甲烷 :V 甲醇 The mixture was recrystallized at a ratio of 10:1 and dried under vacuum at 40°C for 12 hours to obtain the reinforcing agent; its 1H NMR data are as follows: 1 H NMR (400 MHz, DMSO- d 6) δ7.91 (s, 6H), 7.23-7.15 (m, 6H), 6.94-6.86 (m, 6H), 4.84 (s, 3H), 4.26 (q, J= 12.4 Hz, 6H), 3.71-3.50 (m, 114H), 3.30 (s, 9H), 3.09-2.90 (m, 12H), 2.65 (d, J = 4.3 Hz, 6H).

[0046] Example 2: Preparation of the reinforcing agent:

[0047] S1: Under nitrogen protection, 250 ml DMF, 0.1 mol tris(4-hydroxyphenyl)amine, 0.308 mol epichlorohydrin, and 9 mmol tetrabutylammonium bromide were stirred and mixed thoroughly. The mixture was reacted at 85 °C for 4 h, cooled to 65 °C, and 60 g of 20 wt% sodium hydroxide solution was slowly added dropwise over 50 min. The mixture was then cooled to room temperature and the reaction was continued for 12 h. The mixture was then distilled under reduced pressure at 70 °C for 1 h. 500 ml of cold n-hexane was added and stirred to precipitate the precipitate. The precipitate was filtered, washed with deionized water (3 × 100 ml), and dried under vacuum at 70 °C for 12 h to obtain tris[4-(epoxypropane-2-ylmethoxy)phenyl]amine.

[0048] S2: Mix 1000 ml anhydrous DMF, 0.1 mol tris[4-(epoxypropane-2-ylmethoxy)phenyl]amine, 0.315 mol 2,5,8,11,14,17,20,23,26,29-decoxatrione-31-thiol, and 0.31 mol triethylamine. Heat to 65 °C and react for 4 h. Cool to room temperature. Add 1200 ml deionized water to the reaction mixture and extract with dichloromethane (3 × 400 ml). Combine the organic phases and extract with 200 ml of dichloromethane sequentially. The product was washed with 5wt% dilute hydrochloric acid solution, 200ml saturated sodium bicarbonate solution, and 200ml saturated brine. After drying with 20g anhydrous sodium sulfate, the product was filtered and rotary evaporated at 35℃ for 2h to obtain the crude product. The crude product was dissolved in 400ml ethyl acetate, and 800ml cold n-hexane was slowly added and stirred to precipitate the product. The product was filtered, and the filter cake was washed with cold n-hexane (3×100ml). The product was then dried under vacuum at 45℃ for 12h to obtain the sulfide compound.

[0049] S3: Under nitrogen protection, 1200 ml of anhydrous tetrahydrofuran, 0.1 mol of thioether compound, and 0.32 mol of phosphorylated acetic acid were stirred and mixed. Then, 0.32 mol of dicyclohexylcarbodiimide and 0.06 mol of 4-dimethylaminopyridine were added, and the mixture was stirred for 15 min. The reaction was carried out at 25 °C for 17 h. After filtration, 2000 ml of cold n-hexane was added to the filtrate, and the mixture was stirred to precipitate the precipitate. After filtration, the filter cake was treated with a cold methanol-water mixture (V... 甲醇 :V 水Wash with a 4:1 ratio (3 x 100 ml) solution, followed by 600 ml of a dichloromethane and methanol mixture (V... 二氯甲烷 :V 甲醇 The mixture was recrystallized at a ratio of 10:1 and dried under vacuum at 40°C for 12 hours to obtain the reinforcing agent.

[0050] Example 3: Preparation of the reinforcing agent:

[0051] S1: Under nitrogen protection, 250 ml DMF, 0.1 mol tris(4-hydroxyphenyl)amine, 0.31 mol epichlorohydrin, and 9 mmol tetrabutylammonium bromide were stirred and mixed thoroughly. The mixture was reacted at 90 °C for 3 h, cooled to 65 °C, and 60 g of 20 wt% sodium hydroxide solution was slowly added dropwise over 50 min. The mixture was then cooled to room temperature and the reaction was continued for 12 h. The mixture was then distilled under reduced pressure at 70 °C for 1 h. 500 ml of cold n-hexane was added and stirred to precipitate the precipitate. The precipitate was filtered, washed with deionized water (3 × 100 ml), and dried under vacuum at 70 °C for 12 h to obtain tris[4-(epoxypropane-2-ylmethoxy)phenyl]amine.

[0052] S2: Mix 1000 ml anhydrous DMF, 0.1 mol tris[4-(epoxypropane-2-ylmethoxy)phenyl]amine, 0.32 mol 2,5,8,11,14,17,20,23,26,29-decaoxane-31-thiol, and 0.31 mol triethylamine. Heat to 70 °C and react for 3 h. Cool to room temperature. Add 1200 ml deionized water to the reaction mixture and extract with dichloromethane (3 × 400 ml). Combine the organic phases and extract with 200 ml of dichloromethane sequentially. The product was washed with 5wt% dilute hydrochloric acid solution, 200ml saturated sodium bicarbonate solution, and 200ml saturated brine. After drying with 20g anhydrous sodium sulfate, the product was filtered and rotary evaporated at 35℃ for 2h to obtain the crude product. The crude product was dissolved in 400ml ethyl acetate, and 800ml cold n-hexane was slowly added and stirred to precipitate the product. The product was filtered, and the filter cake was washed with cold n-hexane (3×100ml). The product was then dried under vacuum at 45℃ for 12h to obtain the sulfide compound.

[0053] S3: Under nitrogen protection, 1200 ml of anhydrous tetrahydrofuran, 0.1 mol of thioether compound, and 0.33 mol of phosphorylated acetic acid were stirred and mixed. Then, 0.33 mol of dicyclohexylcarbodiimide and 0.06 mol of 4-dimethylaminopyridine were added, and the mixture was stirred for 15 min. The reaction was carried out at 30 °C for 16 h. After filtration, 2000 ml of cold n-hexane was added to the filtrate, and the mixture was stirred to precipitate the precipitate. After filtration, the filter cake was treated with a cold methanol-water mixture (V... 甲醇 :V 水 Wash with a 4:1 ratio (3 x 100 ml) solution, followed by 600 ml of a dichloromethane and methanol mixture (V... 二氯甲烷 :V 甲醇 The mixture was recrystallized at a ratio of 10:1 and dried under vacuum at 40°C for 12 hours to obtain the reinforcing agent.

[0054] Example 4: Preparation of antibacterial agent:

[0055] N1: Under nitrogen protection and in an ice bath, 300 ml of anhydrous DMF, 0.1 mol of 2-quinolinehexanoic acid, 22.9 g of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, and 12.7 g of N-hydroxysuccinimide were mixed and stirred for 45 min to obtain an activated 2-quinolinehexanoic acid DMF solution. The activated 2-quinolinehexanoic acid DMF solution was slowly added dropwise to 120 ml of anhydrous DMF solution containing 0.105 mol of 9-octadeceneamine over 1 h. The reaction was carried out at 25 °C for 9 h (the pH of the solution was maintained between 5.5 and 6 during the reaction using 0.1 M HCl / NaOH solution). The mixture was slowly poured into 500 ml of cold n-hexane and stirred to precipitate. The precipitate was filtered, and the filter cake was washed with cold n-hexane (3 × 80 ml) and dried under vacuum at 65 °C for 12 h to obtain intermediate 1. Its proton NMR spectrum is shown below. Figure 1 As shown, the proton NMR data are as follows: 1 H NMR (400 MHz, Chloroform- d ) δ 8.04-7.97 (m, 2H), 7.76 (d, J = 2.9Hz, 1H), 7.61 (s, 1H), 7.51 (d, J = 4.3 Hz, 1H), 7.12 (d, J = 3.6 Hz, 1H), 6.32 (d, J = 5.4 Hz, 1H), 5.30-5.39 (m, 2H), 3.15 (d, J = 3.6 Hz, 2H), 2.80(s, 2H), 2.15 (s, 2H), 2.02 (s, 4H), 1.61 (d, J = 8.8 Hz, 4H), 1.48 (s, 2H),1.37-1.26 (m, 24H), 0.90 (s, 3H);

[0056] N2: Mix 350 ml of anhydrous dichloromethane and 0.1 mol of intermediate 1 thoroughly. Under ice bath conditions, add 0.12 mol of m-chloroperoxybenzoic acid. Stir for 30 min, then heat to 25 °C and react for 3 h. Wash the reaction solution successively with 100 ml of saturated sodium sulfite solution and 100 ml of saturated sodium bicarbonate solution. Dry with 10 g of anhydrous magnesium sulfate, filter, and rotary evaporate at 35 °C for 1 h to obtain intermediate 2. Its 1H NMR spectrum is shown below. Figure 2 As shown, the proton NMR data are as follows: 1 H NMR (400 MHz, Chloroform- d) δ 8.04-7.97 (m,2H), 7.76 (s, 1H), 7.61 (s, 1H), 7.51 (d, J = 2.5 Hz, 1H), 7.12 (d, J = 2.6Hz, 1H), 6.33 (s, 1H), 3.39 (s, 2H), 3.15 (d, J = 5.7 Hz, 2H), 2.80 (s, 2H),2.15 (s, 2H), 1.76 (d, J = 12.4 Hz, 2H), 1.64-1.56 (m, 6H), 1.48 (d, J = 1.8Hz, 2H), 1.41-1.26 (m, 24H), 0.90 (s, 3H);

[0057] N3: Under nitrogen protection, 250 ml of anhydrous DMF, 0.205 mol of intermediate 2, and 0.205 mol of triethylamine were mixed, and 150 ml of anhydrous DMF solution containing 0.1 mol of 1-methyl-3-(3-aminopropyl)-3-chloroimidazolium was slowly added dropwise over 1 hour. The mixture was then heated to 65°C and reacted for 4 hours. After cooling to room temperature, 300 ml of deionized water was added to the reaction mixture, and the mixture was extracted with dichloromethane (3 x 250 ml). The organic phases were combined and then extracted with 200 ml of dichloromethane solution each time. Wash with 5wt% dilute hydrochloric acid solution, 200ml saturated sodium bicarbonate solution, and 200ml saturated brine. Dry with 15g anhydrous sodium sulfate, filter, and rotary evaporate at 35℃ for 2h to obtain the crude product. Dissolve the crude product in 400ml ethyl acetate, slowly add 600ml cold n-hexane, stir to precipitate, filter, wash the filter cake with cold n-hexane (3×80ml), and vacuum dry at 45℃ for 8h to obtain intermediate 3; its 1H NMR spectrum is shown below. Figure 3 As shown, the proton NMR data are as follows: 1 H NMR (400MHz, Chloroform- d) δ 9.54 (s, 1H), 8.03-7.97 (m, 5H), 7.76 (s, 2H), 7.61 (s,2H), 7.53-7.48 (m, 3H), 7.12 (d, J = 2.6 Hz, 2H), 6.33 (s, 2H), 4.52-4.39 (m,2H), 3.90 (s, 3H), 3.60 (d, J = 5.0 Hz, 2H), 3.57 (d, J = 5.0 Hz, 2H), 3.15(d, J = 5.3 Hz, 4H), 2.86 (s, 2H), 2.80 (s, 4H), 2.72-2.51 (m, 2H), 2.15 (d,J = 4.9 Hz, 6H), 1.67-1.23 (m, 68H), 0.90 (s, 6H);

[0058] N4: Under nitrogen protection and in an ice bath, 300 ml of anhydrous pyridine and 0.21 mol of 2-(3,4,5-trihydroxyphenyl)acetic acid were mixed, and 0.35 mol of acetic anhydride was slowly added dropwise (temperature controlled at 0-5℃, addition over 30 min). The mixture was heated to room temperature and stirred in the dark for 12 h. The reaction solution was poured into 500 ml of ice water and extracted with ethyl acetate (3 × 120 ml). The organic phase was washed with 5 wt% dilute hydrochloric acid until neutral, dried over 20 g of anhydrous magnesium sulfate, and rotary evaporated at 45℃ for 1 h to obtain acetylated 2-(3,4,5-trihydroxyphenyl)acetic acid; under nitrogen protection, 400 ml of anhydrous methyl methacrylate was added... Benzene, 0.1 mol intermediate 3, and 0.005 mol p-toluenesulfonic acid were mixed and heated to 80 °C, stirred for 30 min, and then acetylated 2-(3,4,5-trihydroxyphenyl)acetic acid was added in portions (4 equal portions, 15 min apart) under the dark. The reaction was maintained at 80 °C for 9 h (during which water generated in the reaction was separated using a water separator). The mixture was cooled to room temperature, and 100 ml of saturated sodium bicarbonate solution was added and stirred for 15 min. The mixture was extracted with ethyl acetate (3 × 200 ml), the organic phases were combined, washed with 100 ml of 5 wt% sodium chloride solution, dried over 25 g of anhydrous magnesium sulfate, filtered, and distilled under reduced pressure at 50 °C for 2 h. Then, 300 ml of a methanol-water mixture (V) was added. 甲醇 :V 水 =7:3) and 0.5 mol K2CO3, stirred at 25℃ for 4 h for deacetylation; extracted with ethyl acetate (3×100 ml), rotary evaporated at 40℃ for 1 h, and purified by silica gel column chromatography (V 石油醚 :V 乙酸乙酯 =3:1), dried under vacuum at 50℃ for 3 hours to obtain the antibacterial agent; its proton nuclear magnetic resonance spectrum is as follows. Figure 4 As shown, the proton NMR data are as follows: 1H NMR (400 MHz, Chloroform- d ) δ 9.54 (s, 1H), 8.03-7.97 (m, 5H), 7.76 (s, 2H), 7.61 (s, 2H), 7.54 (s, 4H), 7.52-7.49 (m, 3H), 7.12 (d, J = 2.6 Hz,2H), 6.72 (t, J = 4.5 Hz, 4H), 6.55 (s, 2H), 6.33 (s, 2H), 4.63 (s, 2H), 4.52-4.39 (m, 2H), 3.90 (s, 3H), 3.71-3.51 (m, 4H), 3.15 (d, J = 5.3 Hz, 4H), 3.09 (s, 2H), 2.80 (s, 4H), 2.74-2.52 (m, 2H), 2.15 (d, J = 3.7 Hz, 6H), 1.71-1.24 (m, 68H), 0.90 (s, 6H).

[0059] Example 5: Preparation of absorbable soft artificial bone material:

[0060] (1) Weigh the following by weight: 30g of bioactive glass, 20g of collagen (recombinant human collagen), 10g of reinforcing agent (prepared in Example 1), 1g of antibacterial agent (prepared in Example 4), 5g of pore-forming agent (sodium chloride), and 100g of deionized water;

[0061] (2) Mix deionized water with collagen and stir at 500 rpm for 20 min. Add bioactive glass, reinforcing agent, antibacterial agent and pore-forming agent and stir at 500 rpm for 30 min to form a slurry. Pour the slurry into a polytetrafluoroethylene mold with dimensions of 200 mm × 200 mm × 40 mm, degas under vacuum (-0.08 MPa, 40 ℃) for 20 min, freeze dry at -50 ℃ for 24 h, and demold to obtain absorbable soft artificial bone material.

[0062] Example 6: Preparation of absorbable soft artificial bone material:

[0063] (1) Weigh the following by weight: 45g of bioactive glass, 35g of collagen (recombinant human collagen), 20g of reinforcing agent (prepared in Example 2), 2g of antibacterial agent (prepared in Example 4), 8g of pore-forming agent (sodium chloride), and 140g of deionized water;

[0064] (2) Mix deionized water with collagen and stir at 500 rpm for 20 min. Add bioactive glass, reinforcing agent, antibacterial agent and pore-forming agent and stir at 500 rpm for 30 min to form a slurry. Pour the slurry into a polytetrafluoroethylene mold with dimensions of 200 mm × 200 mm × 40 mm, degas under vacuum (-0.08 MPa, 40 ℃) for 20 min, freeze dry at -50 ℃ for 24 h, and demold to obtain absorbable soft artificial bone material.

[0065] Example 7: Preparation of absorbable soft artificial bone material:

[0066] (1) Weigh the following by weight: 60g of bioactive glass, 50g of collagen (recombinant human collagen), 30g of reinforcing agent (prepared in Example 3), 3g of antibacterial agent (prepared in Example 4), 10g of pore-forming agent (sodium chloride), and 180g of deionized water;

[0067] (2) Mix deionized water with collagen and stir at 500 rpm for 20 min. Add bioactive glass, reinforcing agent, antibacterial agent and pore-forming agent and stir at 500 rpm for 30 min to form a slurry. Pour the slurry into a polytetrafluoroethylene mold with dimensions of 200 mm × 200 mm × 40 mm, degas under vacuum (-0.08 MPa, 40 ℃) for 20 min, freeze dry at -50 ℃ for 24 h, and demold to obtain absorbable soft artificial bone material.

[0068] Comparative Example 1

[0069] The raw material composition and preparation method of the absorbable soft artificial bone material are basically the same as those in Example 6, except that the reinforcing agent is replaced with an equal weight of the reinforcing agent prepared by the following method:

[0070] The preparation method of the reinforcing agent is basically the same as that in Example 2, except that the tris(4-hydroxyphenyl)amine in step S1 is replaced with an equimolar amount of phloroglucinol.

[0071] Comparative Example 2

[0072] The raw material composition and preparation method of the absorbable soft artificial bone material are basically the same as those in Example 6, except that the reinforcing agent is replaced with an equal weight of the reinforcing agent prepared by the following method:

[0073] The preparation method of the reinforcing agent is basically the same as that in Example 2, except that 2,5,8,11,14,17,20,23,26,29-decoxatridecane-31-thiol in step S2 is replaced with an equimolar amount of 2,5,8,11-tetraoxatridecane-13-thiol.

[0074] Comparative Example 3

[0075] The raw material composition and preparation method of the absorbable soft artificial bone material are basically the same as those in Example 6. The difference is that the reinforcing agent is replaced with a physical mixture of 6g of the thioether compound prepared in Example 2 and 14g of phosphorylated acetic acid.

[0076] Comparative Example 4

[0077] The raw material composition and preparation method of the absorbable soft artificial bone material are basically the same as in Example 6, except that the antibacterial agent is replaced with an equal weight of an antibacterial agent prepared by the following method:

[0078] The preparation method of the antibacterial agent is basically the same as that in Example 4, except that 2-quinoline hexanoic acid in step N1 is replaced with an equimolar amount of 5,6,7,8-tetrahydro-2-naphthoic acid (CAS No.: 2656-00-0).

[0079] Comparative Example 5

[0080] The raw material composition and preparation method of the absorbable soft artificial bone material are basically the same as in Example 6, except that the antibacterial agent is replaced with an equal weight of an antibacterial agent prepared by the following method:

[0081] The preparation method of the antibacterial agent is basically the same as that in Example 4, except that 9-octadeceneamine in step N1 is replaced with an equimolar amount of 3-butene-1-amine.

[0082] Comparative Example 6

[0083] The raw material composition and preparation method of the absorbable soft artificial bone material are basically the same as in Example 6, except that the antibacterial agent is replaced with an equal weight of an antibacterial agent prepared by the following method:

[0084] The preparation method of the antibacterial agent is basically the same as that in Example 4, except that the amount of intermediate 2 in step N3 is replaced with 0.105 mol and the amount of triethylamine is replaced with 0.105 mol; and the amount of 2-(3,4,5-trihydroxyphenyl)acetic acid in step N4 is replaced with 0.11 mol.

[0085] Comparative Example 7

[0086] The raw material composition and preparation method of the absorbable soft artificial bone material are basically the same as in Example 6, except that the antibacterial agent is replaced with an equal weight of an antibacterial agent prepared by the following method:

[0087] The preparation method of the antibacterial agent is basically the same as that in Example 4, except that 2-(3,4,5-trihydroxyphenyl)acetic acid in step N4 is replaced with an equimolar amount of p-hydroxyphenylacetic acid.

[0088] The bioactive glass used in the embodiments and comparative examples of this application is medical grade HQ-BG45s-D1, produced by Kunshan Huaqiao Science and Technology New Materials Co., Ltd.; the recombinant human collagen is recombinant type III humanized collagen, produced by Zhuhai Jibaikang Biotechnology Co., Ltd.; the CAS number of tris(4-hydroxyphenyl)amine is 25926-14-1; and the CAS number of 2-quinolinococcal acid is 3297-63-0.

[0089] The compressive strength, fracture toughness, and antibacterial properties of the absorbable soft artificial bone materials prepared in Examples 5-7 and Comparative Examples 1-7 were tested, and the test results are shown in Table 1.

[0090] Compressive strength test: The absorbable soft artificial bone materials prepared in Examples 5-7 and Comparative Examples 1-7 were cut into cylindrical specimens with a diameter of 5 mm and a height of 10 mm. The specimens were placed on the platform of an electronic dynamic and static universal testing machine, and the compressive strength was tested at a compression rate of 1 mm / min. The compressive strength was calculated according to the following formula: Compressive strength = Maximum pressure when the specimen is compressed to the point of fracture (N) / Sample bottom area (mm²) 2 Each sample was tested 5 times and the average value was taken.

[0091] Fracture toughness test: The absorbable soft artificial bone materials prepared in Examples 5-7 and Comparative Examples 1-7 were cut into 10mm × 10mm × 6mm (length × width × height) specimens. The top part to be measured was ground flat, and an indentation was made on the specimen using a microhardness tester. The holding time was 15s. The values ​​of a, c, and d of the indentation were measured using an IBAS-2 image analyzer and substituted into the formula: (K) IC — Fracture toughness, MPa·m 1 / 2 E—Young's modulus, GPa, approximately 118 GPa; H—Microhardness, GPa, H=0.1891 P / d 2 d—average length of the indentation diagonal, mm; a—half the length of the indentation diagonal, mm; c—half the length of the surface crack, mm; P—load, N), calculate K. IC The value of .

[0092] Antibacterial performance test: The absorbable soft artificial bone materials prepared in Examples 5-7 and Comparative Examples 1-7 were cut into samples with a diameter of 9 mm and a thickness of 2 mm. These samples were placed in capped glass bottles containing PBS buffer (0.1 M, pH=7.4) and autoclaved at 120°C for 15 min. After cooling under ventilation, they were further sterilized by UV irradiation in a clean bench for 1 h. The tested bacterial species was Staphylococcus aureus. Individual colonies were picked from the test strain and diluted with 0.9 wt% physiological saline to a bacterial concentration of 10. 8CFU / ml. Add 100 μl of bacterial suspension to LB solid medium, spread the bacterial suspension evenly with a spreader, place the cut test sample in the medium, seal it, and place the petri dish in a 37℃ biochemical incubator for constant temperature incubation. After 24 hours, take it out to observe the bacterial growth on the medium and record the size of the inhibition zone.

[0093] Table 1 Performance Test Data

[0094]

[0095] As can be seen from the data in Table 1, the absorbable soft artificial bone materials prepared in Examples 5-7 of this application have good compressive strength, fracture toughness, and excellent antibacterial properties.

[0096] The absorbable soft artificial bone materials prepared in Examples 5-7 of this application exhibit good compressive strength and fracture toughness, mainly due to the addition of reinforcing agents containing a rigid triphenylamine structure, a long flexible ether chain structure, and phosphoryl groups. The rigid triphenylamine structure provides skeletal support, reduces the free volume of chain segments, restricts macroscopic deformation, and enhances stress transmission capacity, thereby increasing the compressive strength of the bone material. The long flexible ether chain structure has high chain segment mobility, enabling stress dissipation and thus improving the fracture toughness of the bone material. The phosphoryl groups react with Ca dissolved from the bioactive glass... 2+ The / Si-OH structure forms a Ca-P-Si mineralization transition layer, significantly improving interfacial bonding and osteogenic induction. The various structures in the reinforcing agent achieve enhanced compressive strength, improved toughness, and strong inorganic-organic interfacial bonding through a triple synergistic structure regulation of rigidity, flexibility, and mineralization induction. The reinforcing agent used in Comparative Example 1 has weaker rigidity than the example, resulting in reduced stress transmission capacity and a decrease in the compressive strength of the bone material. The reinforcing agent used in Comparative Example 2 has a shorter flexible ether chain structure than the example, resulting in reduced stress dissipation capacity and a decrease in the fracture toughness of the bone material.

[0097] The absorbable soft artificial bone materials prepared in Examples 5-7 of this application exhibit excellent antibacterial properties, mainly due to the addition of antibacterial agents containing imidazolium cations, long-chain alkyl groups, quinoline heterocyclic structures, and multiple phenolic hydroxyl groups. Specifically, the imidazolium cations carry a positive charge and can interact strongly with the negative charge on the bacterial membrane surface, inserting into the membrane structure and disrupting membrane integrity; the hydrophobic effect of the long-chain alkyl groups allows them to penetrate deep into the hydrophobic core of the bacterial cell membrane, exacerbating membrane structural disorder and forming a synergistic membrane-breaking effect with the imidazolium cations; the nitrogen atom in the quinoline heterocyclic structure can react with Fe... 2+ Mg 2+The presence of metal ions in the antibacterial agent inhibits key bacterial metabolic enzymes; the presence of multiple phenolic hydroxyl groups effectively disrupts bacterial cell membranes and inhibits biofilm formation. The combined effect of these groups enhances the antibacterial properties of the absorbable soft artificial bone material. In Comparative Example 6, the number of long-chain alkyl groups and phenolic hydroxyl groups in the antibacterial agent was reduced, weakening its ability to disrupt cell membranes and resulting in a decrease in the antibacterial properties of the prepared absorbable soft artificial bone material.

[0098] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention. However, any modifications, alterations, and variations made by those skilled in the art without departing from the scope of the present invention based on the disclosed technical content are equivalent embodiments of the present invention. Furthermore, any modifications, alterations, and variations made to the above embodiments based on the essential technology of the present invention are still within the protection scope of the present invention.

Claims

1. An absorbable soft bone material, characterized by comprising: a collagen fiber; and a calcium phosphate compound. The raw materials include the following components by weight: biological active glass 30-60 parts, collagen 20-50 parts, reinforcing agent 10-30 parts, antibacterial agent 1-3 parts, pore-forming agent 5-10 parts, deionized water 100-180 parts; The reinforcing agent is prepared by the following method: S1: tri(4-hydroxyphenyl)amine reacts with epichlorohydrin to form tri[4-(epoxypropane-2-ylmethoxy)phenyl]amine, S2: tri[4-(epoxypropane-2-ylmethoxy)phenyl]amine reacts with 2,5,8,11,14,17,20,23,26,29-decaoxatriacontane-31-thiol to form a sulfide compound, S3: the sulfide compound reacts with phosphonoacetic acid to form the reinforcing agent; The antibacterial agent is prepared by the following method: N1: 2-quinoline hexanoic acid reacts with 9-octadecenylamine to form intermediate 1, N2: intermediate 1 reacts with meta-chloroperoxybenzoic acid to form intermediate 2, N3: intermediate 2 reacts with 1-methyl-3-(3-aminopropyl)-3-chloroimidazolium to form intermediate 3, N4: intermediate 3 reacts with 2-(3,4,5-trihydroxyphenyl)acetic acid to form the antibacterial agent.

2. The absorbable soft bone material according to claim 1, wherein In step S1, the molar ratio of tri(4-hydroxyphenyl)amine to epichlorohydrin is 1:(3.05-3.1).

3. The absorbable soft bone material according to claim 1, wherein In step S2, the molar ratio of tri[4-(epoxypropane-2-ylmethoxy)phenyl]amine to 2,5,8,11,14,17,20,23,26,29-decaoxatriacontane-31-thiol is 1:(3.1-3.2).

4. The absorbable soft bone material according to claim 1, wherein In step S3, the molar ratio of the sulfide compound to phosphonoacetic acid is 1:(3.1-3.3).

5. The absorbable soft bone material according to claim 1, wherein In step N1, the molar ratio of 2-quinoline hexanoic acid to 9-octadecenylamine is 1:1.

05.

6. The absorbable soft bone material according to claim 1, wherein In step N2, the molar ratio of intermediate 1 to meta-chloroperoxybenzoic acid is 1:1.

2.

7. The absorbable soft bone material according to claim 1, wherein In step N3, the molar ratio of intermediate 2 to 1-methyl-3-(3-aminopropyl)-3-chloroimidazolium is 2.05:

1.

8. The absorbable soft bone material according to claim 1, wherein In step N4, the molar ratio of intermediate 3 to 2-(3,4,5-trihydroxyphenyl)acetic acid is 1:2.

1.

9. The absorbable soft bone material according to claim 1, wherein The collagen is recombinant human collagen; the pore-forming agent is sodium chloride.

10. A method for producing the absorbable soft bone material as claimed in any one of claims 1 to 9, characterized by, The method includes the following steps: (1) The following components are weighed by weight parts: biological active glass 30-60 parts, collagen 20-50 parts, reinforcing agent 10-30 parts, antibacterial agent 1-3 parts, pore-forming agent 5-10 parts, deionized water 100-180 parts; (2) The deionized water is stirred with the collagen to form a uniform mixture, and the biological active glass, reinforcing agent, antibacterial agent, and pore-forming agent are added and stirred to form a slurry; the slurry is injected into a polytetrafluoroethylene mold, vacuum degassing, freeze-drying, and demolding to obtain an absorbable soft artificial bone material.

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